B lymphocytes are required for host defense against infectious pathogens but abnormal activation of B cells can lead to autoimmunity. Thus, B cells are important in a wide range of physiologic and pathophysiologic processes. Mature B cells in the spleen enter into one of two compartments, the marginal zone or the follicular. Marginal zone B cells are responsible for rapid responses to pathogens that have reached the circulation. Follicular B cells are recruited into germinal centers, where affinity maturation and the generation of memory B cells lead to heightened responses upon subsequent encounters with a pathogen, which is crucial to immunization by vaccines. Mice lacking CD19, a B cell surface receptor, fail to form marginal zone B cells or germinal centers and have a propensity to produce autoantibodies. Our new data demonstrate that lack of marginal zone B cells results in defects in other components of the marginal zone, including marginal zone macrophages and dendritic cells. However, the macrophages and dendritic cells reappear following reconstitution of the marginal zone B cells by adoptive transfer of wild type B cells. Aim 1 will dissect the mechanisms by which CD19 on B cells regulates the differentiation of MZ B cells, and thereby other constituents of the marginal zone. Additional new preliminary data suggest that that failure to form germinal centers is associated with a failure of activation of Follicular Dendritic Cells (FDC) in CD19-/- mice. Adoptive transfer of wild type B cells also reconstitutes the ability to activate FDC in CD19-/- recipient mice, which recover the ability to form germinal centers. In Aim 2, we will test three hypotheses as to how CD19- dependent mechanisms regulate FDC: through activation of follicular B cells, through effects on the marginal zone that control delivery of antigen to FDC, and through formation of immune complexes. In Aim 3, we will determine how CD19 regulates autoimmunity by experiments to test the role of CD19 in central selection, selection in the periphery, and in a model of autoimmunity. These aims are proposed not just to understand the function of CD19, but to use CD19 to probe basic mechanisms that are fundamental to immunization and protection from pathogens, without autoimmunity. Public Health Relevance: The marginal zone of the spleen is required for survival of infections that have reached the blood while germinal centers are of fundamental importance in vaccination and immunological memory. Despite their crucial roles in protection from infections, the marginal zone and the germinal center responses are poorly understood. This project will use CD19, a protein expressed on B lymphocytes that is required for both types of response, as a tool to investigate the functions of B cells in the marginal zone and in germinal centers in vivo.